Abstract：
Although bile acids play a notable role in depression, the pathological significance of the bile acid TGR5 membrane-type receptor in this disorder remains elusive. Using depression models of chronic social defeat stress and chronic restraint stress in male mice, we found that TGR5 in the lateral hypothalamic area (LHA) predominantly decreased in GABAergic neurons, the excitability of which increased in depressive-like mice. Upregulation of TGR5 or inhibition of GABAergic excitability in LHA markedly alleviated depressive-like behavior, whereas down-regulation of TGR5 or enhancement of GABAergic excitability facilitated stress-induced depressive-like behavior. TGR5 also bidirectionally regulated excitability of LHA GABAergic neurons via extracellular regulated protein kinases-dependent Kv4.2 channels. Notably, LHA GABAergic neurons specifically innervated dorsal CA3 (dCA3) CaMKIIα neurons for mediation of depressive-like behavior. LHA GABAergic TGR5 exerted antidepressant-like effects by disinhibiting dCA3 CaMKIIα neurons projecting to the dorsolateral septum (DLS). These findings advance our understanding of TGR5 and the LHAGABA→dCA3CaMKIIα→DLSGABA circuit for the development of potential therapeutic strategies in depression.
摘要：
虽然胆汁酸在抑郁症中起着显著的作用，胆汁酸TGR5膜型受体在该疾病中的病理意义仍然难以捉摸。使用雄性小鼠慢性社会失败应激和慢性束缚应激的抑郁模型，我们发现，TGR5在下丘脑外侧区（LHA）主要减少在GABA能神经元，抑郁样小鼠的兴奋性增加。LHA中TGR5的上调或GABA能兴奋性的抑制可显着缓解抑郁样行为，而TGR5的下调或GABA能兴奋性的增强促进了应激诱导的抑郁样行为。TGR5还通过细胞外调节蛋白激酶依赖性Kv4.2通道双向调节LHAGABA能神经元的兴奋性。值得注意的是,LHAGABA能神经元特异性神经支配背侧CA3（dCA3）CaMKIIα神经元，以介导抑郁样行为。LHAGABA能TGR5通过抑制投射到背外侧间隔（DLS）的dCA3CaMKIIα神经元而发挥抗抑郁样作用。这些发现促进了我们对TGR5和LHAGABA→dCA3CaMKIIα→DLSGABA电路的理解，以开发抑郁症的潜在治疗策略。
